Nitrosated and nitrosylated compounds, and compositions and their use for treating respiratory disorders

Abstract

Disclosed are (i) compounds of a steroid, a β-agonist, an anticholinergic, a mast cell stabilizer and a phosphodiesterase (PDE) inhibitor directly or indirectly linked to a NO or NO 2 group or a group which stimulates endogenous production of NO or EDRF in vivo; (ii) compositions of steroids, β-agonists, anticholinergics, mast cell stabilizers and PDE inhibitors, which can optionally be substituted with at least one NO or NO 2 moiety or a group which stimulates endogenous production of NO or EDRF in vivo, and a compound that donates, transfers or releases nitric oxide as a charged species, i.e., nitrosonium (NO + ) or nitroxyl (NO − ), or as the neutral species, nitric oxide (NO) or that stimulates endogenous production of NO or EDRF in vivo; and (iii) uses for them in preventing and/or treating respiratory disorders.

What is claimed is:  
     
       1. A compound having the structure:                    
       wherein 
       A is selected from  —CH═CH— or —CH 2 —CH 2 —;  
       R 1  is selected from  hydrogen or —C(O)CH 2 —B—D, wherein B is oxygen or  sulfur and D is selected from (i) hydrogen, (ii)  —NO and (iii)  or —NO 2 ; with the provision that when B is oxygen then D is H or —NO ;  
       R 2  and R 3  are independently selected from hydrogen, hydroxyl, lower alkyl, —O(O)C—R i , or —S—R i  wherein R i  is hydrogen, lower alkyl or lower haloalkyl, or when taken together are:                    
       wherein R i   1  and R i   2  are independently selected from R i  wherein R i  is defined as above; 
       R 4  and R 5  are independently selected from hydrogen or halogen;  
       R 6  is selected from hydrogen, —NO, —NO 2  and —C(O)CH 2 —B—D, wherein B is oxygen or sulfur and D is selected from hydrogen, —NO and —NO 2 , with the provision when R 1  is hydrogen, or the D group of R 1  is hydrogen or —NO, with the B group being oxygen  then R 6  is selected from the group consisting of —NO, NO 2  and —C(O)CH 2 —B—D, wherein B is oxygen or sulfur and D is —NO or —NO 2 ;  
       or an ester or thioester of said compound .  
     
     
       2. A compound according to claim  1 , wherein A is —CH═CH—. 
     
     
       3. A compound according to claim  1 , wherein A is —CH 2 —CH 2 —. 
     
     
       4. A compound according to claim  2 , wherein B in the definition of R 6  is oxygen. 
     
     
       5. A compound according to claim  4 , wherein R 2  and R 3  taken together are:                    
       wherein R i   1  and R i   2  are independently hydrogen or lower alkyl. 
     
     
       6. A compound according to claim  5 , wherein R i   1  and R i   2  are each methyl. 
     
     
       7. A compound according to claim  4 , wherein R 4  and/or R 5  are independently selected from hydrogen, a chloro group or a fluoro group. 
     
     
       8. A compound according to claim  7 , wherein R 2  is hydroxy, R 3  is methyl, R 4  is a chloro group and R 5  is hydrogen. 
     
     
       9. A compound according to claim  7 , wherein R 2  is hydroxy, R 3  is hydroxy, R 4  is a fluoro group and R 5  is hydrogen. 
     
     
       10. A compound according to claim  1 , wherein R 1  is hydrogen, or the D group of R 1  is hydrogen or  —NO, and R 6  is selected from the group consisting of —NO, NO 2  and —C(O)CH 2 —B—D, wherein B is oxygen or sulfur and D is —NO or —NO 2 . 
     
     
       11. A compound according to claim  1 , wherein the D group of R 1  is —NO, and R 6  is selected from the group consisting of hydrogen and —C(O)CH 2 —B—D, wherein B is oxygen or sulfur and D is hydrogen. 
     
     
       12. A composition comprising a therapeutically effective amount of a compound according to claim  1  and a pharmaceutically acceptable excipient or carrier. 
     
     
       13. A composition comprising a therapeutically effective amount of a compound according to claim  2  and a pharmaceutically acceptable excipient or carrier. 
     
     
       14. A composition comprising a therapeutically effective amount of a compound according to claim  5  and a pharmaceutically acceptable excipient or carrier. 
     
     
       15. A composition comprising a therapeutically effective amount of a compound according to claim  7  and a pharmaceutically acceptable excipient or carrier. 
     
     
       16. A composition comprising a therapeutically effective amount of a compound according to claim  11  and a pharmaceutically acceptable excipient or carrier. 
     
     
       17. A method for treating a respiratory disorder in an individual comprising administering an  a therapeutically effective amount of a compound according to claims  claim  1 . 
     
     
       18. A method for treating asthma in an individual comprising administering an  a therapeutically effective amount of a compound according to claims  claim  1 . 
     
     
       19. A method for treating a respiratory disorder in an individual comprising administering an  a therapeutically effective amount of a compound according to claims  claim  5 . 
     
     
       20. A compound having the structure:                    
       
         wherein:  
       
         A is —CH═CH— or —CH   2   —CH   2 ;  
         R   1    is hydrogen or —C ( O ) CH   2   —B—D, wherein B is oxygen or sulfur and D is hydrogen, —NO or —NO   2 ;  
         R   2    and R   3    are each independently hydrogen, hydroxyl, lower alkyl, —O ( O ) C—R   i   , or —S—R   i    wherein R   i    is hydrogen, lower alkyl or lower haloalkyl, or when taken together are:                      
       
         wherein R 
         i 
         1  
         and R 
         i 
         2  
         are independently selected from R 
         i  
         wherein R 
         i  
         is defined as above;  
       
       
         R 
         4  
         and R 
         5  
         are independently selected from hydrogen or halogen;  
       
         R   6    is —C ( O ) CH   2   —B—D, wherein B is oxygen or sulfur and D is selected from hydrogen, —NO and —NO   2   , with the provision that when the D group of R   6    is hydrogen, then R   1    is not hydrogen and the D group of R   1    is not hydrogen.    
     
     
       21. A compound according to claim  20 , wherein A is —CH═CH—.  
     
     
       22. A compound according to claim  20 , wherein A is —CH 2   —CH   2 —.  
     
     
       23. A compound according to claim  20 , wherein B in the definition of R 1    is oxygen.    
     
     
       24. A compound according to claim  20 , wherein R 2    and R   3    taken together are:                      
       
         wherein R 
         i 
         1  
         and R 
         i 
         2  
         are independently hydrogen or lower alkyl.  
       
     
     
       25. A compound according to claim  20 , wherein R i   1    and R   i   2    are each methyl.    
     
     
       26. A compound according to claim  20 , wherein at least one R 4    and R   5    are independently selected from hydrogen, a chloro group or a fluoro group.    
     
     
       27. A compound according to claim  20 , wherein R 2    is hydroxy, R   3  is methyl, R 4    is a chloro group and R   5    is hydrogen.    
     
     
       28. A compound according to claim  20 , wherein R 2    is hydroxy, R   3    is hydroxy, R   4    is a fluoro group and R   5    is hydrogen.    
     
     
       29. A composition comprising a therapeutically effective amount of a compound of claim  20  and a pharmaceutically acceptable excipient or carrier.  
     
     
       30. A method for treating a respiratory disorder in an individual comprising administering a therapeutically effective amount of the composition of claim  29 .  
     
     
       31. A method for treating asthma in an individual comprising administering a therapeutically effective amount of the composition of claim  29 .  
     
     
       32. A compound according to claim  20 , wherein B in the definition of R 6    is oxygen.    
     
     
       33. A compound according to claim  20 , wherein B in the definition of R 1    is oxygen and D in the definition of R   1    is hydrogen or —NO.    
     
     
       34. A method for treating asthma in an individual comprising administering a therapeutically effective amount of the composition of claim  12 .  
     
     
       35. A method for treating a respiratory disorder in an individual comprising administering a therapeutically effective amount of the composition of claim  12 .  
     
     
       36. The method of claim  35 , wherein the respiratory disorder is pneumonia, traumatic injury, aspiration or inhalation injury, fat embolism in the lung, acidosis, inflammation of the lung, adult respiratory distress syndrome, acute pulmonary edema, acute mountain sickness, asthma, post cardiac surgery, acute pulmonary hypertension, persistent pulmonary hypertension of the newborn, perinatal aspiration syndrome, hyaline membrane disease, acute pulmonary thromboembolism, heparin- protamine reactions, sepsis, status asthmaticus, hypoxia, chronic pulmonary hypertension, bronchopulmonary dysplasia, chronic pulmonary thromboembolism, idiopathic pulmonary hypertension, primary pulmonary hypertension or chronic hypoxia.    
     
     
       37. A method of treating cystic fibrosis in an individual comprising administering a therapeutically effective amount of the composition of claim  12 .  
     
     
       38. The method of claim  30 , wherein the respiratory disorder is pneumonia, traumatic injury, aspiration or inhalation injury, fat embolism in the lung, acidosis, inflammation of the lung, adult respiratory distress syndrome, acute pulmonary edema, acute mountain sickness, asthma, post- cardiac surgery, acute pulmonary hypertension, persistent pulmonary hypertension of the newborn, perinatal aspiration syndrome, hyaline membrane disease, acute pulmonary thromboembolism, heparin - protamine reactions, sepsis, status asthmaticus, hypoxia, chronic pulmonary hypertension, bronchopulmonary hysplasia, chronic pulmonary thromboembolism, idiopathic pulmonary hypertension, primary pulmonary hypertension or chronic hypoxia.    
     
     
       39. A method of treating cystic fibrosis in an individual comprising administering a therapeutically effective amount of the composition of claim  29 .